Each year in the United States, approximately eight million people present to a hospital emergency room (ER) with chest pain suggestive of cardiac origin (Storrow et al. (2000) Ann. Emerg. Med. 35:449), and even more present to their primary care physician. Acute Coronary Syndrome (ACS) presents as a constellation of symptoms such as chest pain, shortness of breath, inability to maintain physical exertion, sense of dread, pain or tingling on the left arm, and may also be accompanied by clinical signs such as altered electrocardiogram and elevation in biochemical markers of necrosis such as cardiac troponin. Chest pain of suspected cardiac origin is often referred to by its clinical description of angina pectoris. Chest pain is the number two reason for emergency room presentation, accounting for about eight percent of all patients.
The chest pain patient presents a diagnostic nightmare for the emergency room physician. On one hand, if the patient really is having a heart attack, early and rapid therapy is crucial to prevent more damage to the heart muscle, and missed diagnosis may result in poor consequences for the patient including death. On the other hand, if the patient is not having a heart attack and the physician keeps the patient in the hospital for a long time performing many diagnostic tests, the patients will consume precious health care resources that could be better spent on others. In fact, it is estimated that diagnosis of chest pain patients represents about $6 billion of wasted resources in the US alone.
The term “infarct” or “infarction” means a region of tissue which is dead and non-functional. For example, it is possible to have a brain infarct as a result of a stroke, or a bowel infarct as a result of severe bowel ischemia. A myocardial infarction (MI) is a region of dead heart muscle which is therefore unable to contribute to the pumping function of the heart. The term “heart attack” usually refers to an acute myocardial infarction or AMI, which is the emerging or developing MI, and is the end stage of ACS.
As a person ages, there is often a buildup of fatty plaque in the coronary arteries. The plaque is usually due to deposition of cholesterol from the blood, and consists of a soft core, with a harder membrane overlying it. At some time, a plaque may become unstable and rupture. A ruptured plaque will trigger a cascade of reactions in the blood, leading to formation of a clot or thrombus. The thrombus may be carried downstream in the coronary artery circulation, which becomes progressively narrower. Eventually, the thrombus will occlude a coronary artery, disrupting circulation and preventing blood supply to the cardiac muscle or myocardium.
Ischemia is the condition of imbalance between oxygen supply and demand. Ischemia can be transitory or continuous. In the case of myocardial ischemia, the oxygen supply is provided by the blood flow in the coronary arteries. The demand may depend on the physical exertion of the person. Thus, ischemia can result from increased demand with a limited supply (e.g.: as a result of increased stress with occluded coronary arteries), or from suddenly restricted supply, as may occur with plaque disruption and thrombus formation in a coronary artery. The first case is often referred to as stable angina. This word “stable” refers to the fact that the angina is reproducible because the restriction in supply is stable (and usually due to stable plaque), and the ischemia can be reversed by simply ceasing the activity. Unstable angina is chest pain which occurs when coronary artery flow is rapidly compromised due to disruption of a plaque (so called unstable plaque) and is inadequate to supply the oxygen demands of the heart during minimal activity. In this case, the ischemia cannot be stopped by ceasing activity, and it may deteriorate to something worse, such as acute myocardial infarction.
Once the blood supply to the myocardium is restricted, the myocardium becomes starved of oxygen, leading to ischemia. In the early stages, the tissue is reversibly ischemic, meaning that with resumption of blood supply the tissue will recover and return to normal function. After a while, the tissue becomes irreversibly ischemic, meaning that although the cells are still alive, if the blood supply is restored, the tissue is beyond salvation, and will inevitably die. Finally, the tissue dies (i.e., becomes necrosed), and forms part of the myocardial infarct. In fact, myocardial infarction is defined as “myocardial cell death due to prolonged ischemia.”
The events which occur in an AMI are illustrated diagramatically in FIG. 1. An occlusion of a coronary artery (1) results in reduced blood flow. Tissue becomes first reversibly ischemic, then irreversibly ischemic, and finally necrosed (dead). The tissue which has been ischemic for the longest time is that which dies first. Because much of the myocardial tissue is supplied via capillaries, regions furthest from the site of occlusion are the last to receive oxygenated blood, and therefore are ischemic for shorter time than the areas closer to the site of occlusion. Thus, there are several zones of conditions proceeding in the tissue downstream from the coronary artery occlusion. The zone furthest away is reversibly ischemic (2), progressing to irreversibly ischemic (3), then finally necrosed (4). Eventually the entire region of tissue becomes necrosed with no remaining ischemic tissue, and there is a complete infarct.
Patients presenting with chest pain may be having stable angina, unstable angina, AMI, non-ischemic cardiac problems such as congestive heart failure, or non-cardiac problems such a gastro esophageal reflux disease (GERD). The optimal therapy for each of these patient types and the urgency for therapy is quite different, hence rapid diagnosis and risk stratification has enormous clinical importance.
Until recently, the diagnosis of an MI was done retrospectively. The criteria established by the World Health Organization (WHO) defined MI as any two of the three characteristics of (a) typical symptoms (i.e., chest discomfort), (b) enzyme rise, and (c) typical ECG pattern involving the development of Q-waves (an indication of necrosed myocardium). With these criteria, which were established some years ago, the “enzyme rise” refers to the rise of serum levels of creatine kinase (CK) or its more cardiac specific isoform CK-MB. CK-MB is one of the molecules released from dead cardiac muscle cells and therefore is a serum marker of necrosis. As a heart muscle cell dies as a result of prolonged ischemia, the cell membrane ruptures, releasing the cytosolic contents into the extracellular fluid space, then into the lymphatic system, and from there it enters the bloodstream.
Since the WHO criteria were first promulgated, new biochemical markers of cardiac necrosis have been discovered and commercialized. (For a complete description of many of these markers, see Wu, A.H.B. (ed.) Cardiac Markers, Humana Press ISBN 0-89603-434-8, 1998). The most specific markers of cardiac necrosis so far developed are the cardiac troponins. These are proteins which are part of the contractile apparatus of myocardial cells. Two versions, cTnI and cTnT have been commercialized, and shown to be very specific for detection of even small amounts of myocardial damage. The cardiac troponins, similar to CK-MB, are released from dead cardiac muscle cells when the cell membrane ruptures, and are eventually detectable in the blood. Necrosis can certainly occur as a result of a prolonged myocardial ischemia, but can also result from myocardial cell damage from other causes such as infection, trauma, or congestive heart failure. Thus, the observation of an increase in cardiac markers of necrosis alone does not lead to a definitive diagnosis of myocardial infarction.
The cardiac markers described above are excellent markers of necrosis, but are not markers of ischemia. However, there is much confusion in the medical community and in the literature on this point, and it is not uncommon to see references to troponin, CK-MB and myoglobin (another marker of cardiac necrosis) being described as markers of cardiac ischemia. Although it is true that necrosis is always preceded by and is a consequence of ischemia, it is not true that ischemia always leads to necrosis. Therefore these necrosis markers are not necessarily markers of ischemia. For example, stable angina is cardiac ischemia as a result of exercise which will not necessarily lead to necrosis. If the person stops exertion, the demand will fall to the level which can be adequately supplied by the circulation, and the ischemia dissipates, and there is thus no elevation of markers of cardiac necrosis.
The American College of Cardiology (ACC) and the European Society of Cardiology (ESC) published a consensus document (Alpert, J. S. et al. (2000) J. Am. Coll. Card. 36:3) with a proposed redefinition of myocardial infarction. Part of the consensus document is a new definition of acute, evolving or emerging MI. The new definition is that either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI:                1. typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis with at least one of the following:                    a. ischemic symptoms;            b. development of pathologic Q-waves on the ECG;            c. ECG changes indicative of ischemia (ST segment elevation or depression); or                        2. coronary artery intervention (e.g., coronary angioplasty); or        3. pathologic findings of acute MI.        
Implicit in this definition is the idea that an AMI includes both an ischemic component and a necrosis component. The problem is that although there are excellent biochemical markers of necrosis (i.e., troponin), there are no accepted biochemical markers of ischemia, and therefore reliance is made on clinical impressions combined with symptoms and changes in the ECG. The fact that troponin is not a marker of ischemia is highlighted in the consensus document which states “these biomarkers reflect myocardial damage but do not indicate its mechanism. Thus an elevated value in the absence of clinical evidence of ischemia should prompt a search for other causes of cardiac damage, such as myocarditis.”
The problem is that cardiac ischemia is extremely difficult to diagnose. The National Heart Lung and Blood Institute (NHLBI) of the U.S. National Institutes of Health (NIH) created a National Heart Attack Alert Program (NHAAP) in the early 1990s. In 1997, a working group of the NHAAP published an evaluation of all technologies available at the time for identifying acute cardiac ischemia in the emergency department (Selker, H. P. et al. (1997) A Report from the National Heart Attack Alert Program (NHAAP) Coordinating Committee Blackwell Science ISBN 0-632-04304-0). The key reason for this report was that new technologies for reperfusion (in particular percutaneous transluminal coronary angioplasty or PTCA, and a whole class of thrombolytic drug therapies such as TPA (tissue plasminogen activator) and streptokinase) had shown that dramatic improvements in mortality and morbidity were related to the interval between the onset of chest pain and the start of therapy. This is clearly because the earlier therapy can be applied, the more of the myocardial tissue is still reversibly ischemic instead of necrosed, and therefore there is higher likelihood that it will recover if blood supply is restored. Obviously, the key to reducing the time to therapy is to improve the performance of diagnostic tests in the emergency department (ED) such that the diagnosis can be made earlier while reversible ischemia is still present. In fact, the introduction of the NHAAP book states that “identifying only AMI would miss a large number of ED patients at significant and immediate cardiac risk.”
The standard of care and the most widely accepted tool for diagnosis of ACS in the ED is the standard twelve lead electrocardiogram (ECG or EKG). Changes such as ST Segment Elevation are indicative of injury to the myocardium, and lead to a diagnosis of MI. Changes such as ST Segment depression are indicative of ischemia. The ECG is also used to diagnose and classify arrhythmias such as atrial fibrillation and ventricular tachycardia. A patient with an arrhythmia such as Left Bundle Branch Block (LBBB) obscured features on the ECG and makes the ECG uninterpretable for ACS.
The ECG suffers from imperfect sensitivity and specificity for acute cardiac ischemia, and when interpreted using stringent criteria for AMI, sensitivity drops to 50% or below. Other tools which have been investigated but not yet well accepted include variations on the ECG or algorithms involving the ECG, cardiac markers such as CK-MB and TnI, radionuclide myocardial perfusion imaging (MPI) using 99Tc sestamibi and thallium, ECG exercise stress test, and ultrasound echocardiography. None of these has been shown to have consistently reliable sensitivity and specificity to the point where it has been accepted as standard of care. Furthermore, some technologies such as MPI, while offering relatively good accuracy, are expensive and have limited availability.
There have been several attempts to develop a device and/or algorithms for diagnosing AMI in chest pain patients using biochemical markers (see, for example, Jackowski, G., U.S. Pat. No. 5,710,008 (1998)). The '008 patent describes a method and a device for using a combination of at least three biochemical markers in conjunction with an algorithm for diagnosis of AMI. Cardiac Troponin has been accepted as the “gold standard” biochemical marker for diagnosis of acute myocardial infarction. The clinical performance of Troponin I has been reported by many publications, and by many manufacturers of troponin assays.
Although troponin is a very specific marker for cardiac necrosis, its clinical utility, especially in the early period following onset of chest pain (i.e., immediately after the coronary artery occlusion leading to ischemia) is limited by the slow kinetics of the marker itself, and the fact that it is a marker for necrosis, not ischemia, and therefore released late in the clinical sequence. In other words, the clinical sensitivity of troponin for detection of AMI approaches 100% provided sufficient time has elapsed. However, the clinical sensitivity of troponin for detection of AMI (or ACS) is less than 20% at presentation of a patient within 2 hours of the onset of chest pain (Mair et al. (1995) Clin. Chem. 41:1266; Antman et al. (1995) JAMA 273:1279). This is important because the median time for presentation to a hospital emergency room after onset of chest pain is about two hours in patients who will be subsequently diagnosed as having AMI (Goff et al. (1999) Am. Heart J. 138:1046).
Attempts to obtain better diagnosis of AMI using combinations of results from biochemical markers of necrosis have been described. For example, Shah et al., U.S. Pat. No. 5,382,515 (1995), describe an algorithm using sequential closely spaced measurements of different isoforms of creatine kinase to determine both the presence and the time of an AMI. The concept was expanded by Groth, T. et al., U.S. Pat. No. 5,690,103 (1997), who describe the use of an algorithm implemented by a neural network whose inputs are several closely spaced measurements of several markers released from necrotic tissue (CK-MB and troponin). Although this method may be beneficial in that it is still better than measurement of a single necrosis marker, or multiple necrosis markers at a single time, it is still not possible to make the determination until at least three hours have passed, and does not work for detection of ischemia since only necrosis markers are used.
A similar approach (although without a neural network) was proposed by Armstrong et al. (U.S. Pat. No. 6,099,469 (2000)), although in this case the algorithm is designed to run on the computer embedded in an automated laboratory analyzer, and suggests which test should be performed next. Again, the Armstrong invention suffers from the limitation that it uses only markers of necrosis, and requires multiple sequential measurements to achieve adequate performance.
Ohman et al. (U.S. Pat. No. 6,033,364 (2000)) described algorithms using combinations of existing markers of necrosis which have also been used to assess reperfusion after thrombolytic therapy. In this invention, an algorithm using sequential measurements of a necrosis marker (CK-MB) and a model based on the rise and fall kinetics of CK-MB can determine when therapy has allowed restoration of coronary artery flow and therefore arrested the growth of infarcted tissue and hence release of further markers of necrosis.
Partly as a result of the difficulty of obtaining a firm diagnosis in chest pain patients, there has been a growing emphasis in clinical medicine in recent years to focus more on risk stratification than a hard diagnostic endpoint. To meet these clinical practice guidelines, emergency physicians need diagnostic tools and procedures that can help identify high risk ACS patients in less than 30 minutes. The concept of a “Chest Pain Evaluation Unit” (CPEU) has gained rapid acceptance in the emergency medicine field. The basic concept is rapid risk stratification based on ECG, clinical presentation, and often troponin, in a hierarchy. High risk patients may receive more aggressive diagnostic testing (e.g.: cardiac catheterization) and therapy (e.g.; anti-coagulant drugs), whereas low risk patients may be relegated to watchful waiting and eventual discharge. Patients who can not be adequately risk stratified at presentation are subjected to serial testing, and often provocative testing such as stress ECG. With currently available tools combining ECG and troponin, only about 25% of patients can be reliably risk stratified at presentation, and the remainder will spend many hours with serial testing and watchful waiting before receiving therapy or being discharged.
One of the problems with early risk stratification of chest pain patients has been the problem of obtaining rapid assessment of biochemical markers such as troponin when the instruments are in a central laboratory, and may not be configured for “stat” utilization. As a result, there has been a growing interest in Point of Care (POC) Testing, often with dedicated instruments placed in the emergency room or near the patient to perform a limited number of diagnostic tests, but to give the results in a short period of time. For example, Anderson et al in U.S. Pat. No. 6,394,952 and U.S. Pat. No. 6,267,722 “Point of Care Diagnostic Systems” describe an apparatus for performing rapid testing and turning the results into diagnostic or risk assessment information.
Interpretation of an electrocardiogram is fraught with error, particularly by physicians who do not perform this task often and routinely. To help solve this problem, electrocardiographic machines have been developed which perform automatic analysis on the ECG, for example to look at deviations of the ECG ST segment to determine if ischemia is present or absent. See U.S. Pat. No. 4,546,776 “Portable EKG Monitoring Device for ST Deviation” for an early example of this technology. Many algorithms have been invented for improving the performance of equipment to detect ST segment changes indicative of cardiac ischemia—see for example U.S. Pat. No. 6,507,753 (2003) “Method and Apparatus to Detect Acute Cardiac Syndromes in Specified Groups of Patients using ECG”, and U.S. Pat. No. 4,930,075 (1990) “Technique to Evaluate Myocardial Ischemia from ECG Parameters”. Alternative parameters in the ECG have been evaluated as a detector for ischemia, including interval data—see for example U.S. Pat. No. 6,361,503 (2002) “Method and System for Evaluating Cardiac Ischemia”. Because of the relatively poor performance of ECG as a signal source for diagnosis of ischemia, there have been attempts to allow the user to “trade off” sensitivity and specificity in the way the algorithms are performed, see for example U.S. Pat. No. 6,171,256 B1 (2001) “Method and Apparatus for Detecting a Condition Associated with Acute Cardiac Ischemia”.
This shift in emphasis from hard diagnosis to risk stratification which has been seen in the recent use of biochemical markers has also had an impact on the world of electrocardiography. Inventions have been directed towards estimating the probability that a patient has cardiac ischemia as opposed to merely providing a “yes” or “no” diagnostic answer. For example, in US Patent Application US2002/0133087A1 (2002), “Patient Monitor for Determining a Probability that a Patient has Acute Cardiac Ischemia”, the inventors use continuously monitored and analyzed ECG signals to provide a numerical probability of acute cardiac ischemia for a patient in an emergency department. A similar objective is targeted in the invention described in European Patent Application EP. 1.179.319.A1 (2001) “Method and Apparatus to Detect Acute Cardiac Syndromes in Specified Groups of Patients using ECG”.
There would be an advantage to providing diagnosis of ACS before a patient presents to an emergency room, for example in an ambulance or in the physician's office. Some inventions have been directed towards improving the performance of ECG analysis in a telemedicine environment—see for example U.S. Pat. No. 6,424,860 “Myocardial Ischemia and Infarction Analysis and Monitoring Method and Apparatus.” There have also been attempts to detect ischemia using an implantable device (see U.S. Pat. No. 6,128,526 “Method for Ischemia Detection and Apparatus Using Same”).
However, the object of the inventions described above is to improve the analytical performance of equipment where the fundamental signal source—ECG—is flawed or inadequate. Thus there is a need to provide more and better tools for emergency medicine physicians, and others, to make more reliable assessment of a patient's risk of cardiac ischemia at presentation, both using existing sources of diagnostic information and, more importantly, combinations of new and existing sources of information.